Abstract
Hepatocyte apoptosis is the main pathophysiological process underlying liver ischemia/reperfusion (I/R) injury. Mitochondrial abnormalities have a vital role in hepatocellular damage. The hepatoprotective effects of mesenchymal stem cells (MSCs) have been previously demonstrated. In this study, we aim to investigate the effect and potential mechanism of MSCs against liver I/R injury. Effects of MSCs were studied in mice liver I/R injury model and in a hypoxia/reoxygenation (H/R) model of L02 hepatocytes. The potential mechanisms of MSCs on these in vivo and in vitro I/R-induced hepatocellular apoptosis models were studies. Accompanied by the improvement of hepatic damage, MSCs exhibited capabilities of controlling mitochondrial quality, shown by reduced mitochondrial reactive oxygen species (mtROS) overproduction, decreased the accumulation of mitochondrial fragmentation, restored ATP generation and upregulated mitophagy. Furthermore, we descripted a potential mechanism of MSCs on upregulating mitophagy and found that the reduced Parkin and PINK1 expression and inactivated AMPKα pathway were observed in the liver tissue in I/R model. These effects were reversed by MSCs treatment. In vitro study showed that MSC-conditioned medium (MSC-CM) suppressed hepatocellular apoptosis and inhibited mtROS accumulation in the H/R environment. And these effects of MSC-CM were partially blocked after the cells were transfected with PINK1 siRNA or added with dorsomorphin. Collectively, our findings provide a novel pharmacological mechanism that MSCs exert hepatoprotective effect in liver I/R injury via upregulating PINK1-dependent mitophagy. In addition, this effect might be attributed to the modulation of AMPKα activation.
Highlights
Liver ischemia/reperfusion (I/R) injury is one of the most important factors that induce liver dysfunction and even mortality during liver transplantation, major liver resection and hemorrhagic shock[1]
The count of autophagic vacuoles in the livers was measured (n = 5). e The autophagy-related proteins in liver tissues obtained from mice with I/R injury after 6 and 24 h of reperfusion and treated with phosphate-buffered saline (PBS) or umbilical cords (UCs)-Mesenchymal stem cells (MSCs) were assessed by a western blotting assay
Our study revealed that administration of umbilical cord-derived MSCs (UC-MSCs) induced hepatocellular mitophagy both in vivo and in vitro, and this effect has a critical role in scavenging of mitochondrial reactive oxygen species (mtROS), reduction of mitochondrial fragmentation and inhibition of cell apoptosis
Summary
Liver ischemia/reperfusion (I/R) injury is one of the most important factors that induce liver dysfunction and even mortality during liver transplantation, major liver resection and hemorrhagic shock[1]. In response to mechanical hypoxic injury, ATP consumption and oxygen deletion induce increased hepatocyte death, whereas reperfusion induces high levels of inflammatory cell infiltration and reactive oxygen species (ROS) overproduction and thereby leads to extensive hepatocellular damage[2,3]. Identification of promising therapeutic strategies for targeting this pathophysiological process is necessary for alleviating liver I/R injury. Mesenchymal stem cells (MSCs) have been gained attention as potential therapy for various diseases due to their capabilities of multipotent differentiation, regeneration and immunomodulation. Administration of MSCs appears to be a promising therapeutic strategy for I/R injury in brain, kidney and heart. Our and other recent studies have shown the role of MSCs in alleviating hepatic dysfunction in a liver I/R model[4,5,6]. Detailed mechanism of hepatoprotective role of MSCs remains not fully understood
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